Neoadjuvant Peptide Receptor Radionuclide Therapy (PRRT) With 90Y-DOTATOC in Pancreatic Neuroendocrine Tumours.
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- objective response evaluation
研究概览
简要总结
Neuroendocrine tumors (NETs) are relatively rare tumors, mainly originating from the digestive system, that tend to be slow growing and are often diagnosed when metastatic. Surgery is the sole curative option, but is feasible only in a minority of patients.
Peptide Receptor Radionuclide Therapy (PRRT) has been experimented for almost 20 years and is an established effective therapeutic modality for well/moderately differentiated, inoperable or metastasized gastro-entero-pancreatic (GEP) and bronchial NETs. Clinical studies demonstrated that partial and complete objective responses can be obtained in up to 30% of patients. Side effects may involve the kidneys and the bone marrow and are usually mild. Renal protection is used to minimize the risk of a late decrease of renal function.
A new application for P-NETs is preoperative PRRT. Since surgery is the only curative option for GEPNETs, preoperative PRRT could increase the efficacy of surgery. However, this modality has not been fully explored in dedicated studies and there are just few sporadic case reports that described the preoperative use of PRRT in pancreatic NETs who could then be operated on successfully. Moreover there are few experiences demonstrating the advantage of PRRT associated to surgery in a multidisciplinary setting. In addition, the possibility of detecting the circulating NET transcripts by means of transcriptome analysis could represent an early marker of response to PRRT and improve the patient management.
Aim of this study is to evaluate the response and rate of R0 surgery in patients with unresectable or borderline resectable PNETs eligible to PRRT with 90Y-DOTATOC and correlate the response to the variation in circulating NET transcripts measured before and after the end of PRRT. It has been recently shown that a PCR-based 51 transcript signature is significantly more sensitive and efficient than single analytes (e.g. CgA) in NET diagnosis and follow up.
30 patients will be enrolled in the study; each of them will receive 1.85 GBq/cycle of 90Y-DOTATOC with a cumulative activity of 9.25-11.1 GBq in 5-6 cycles (depending on personalized dosimetry). Therapy response will be assessed by morphological (CT/MRI) and functional (PET/CT or Octreoscan) imaging after 3 and 6 months from the completion of PRRT and compared with transcript analysis.
Based on literature reports we expect a response rate of about 35% of patients.
详细描述
GEP-NETs tend to be slow growing (although aggressive forms exist) and are often diagnosed when they have already metastasized, when a radical treatment is no longer possible.
Treatment of NETs is typically multidisciplinary and should be individualized according to tumor type, burden, and symptoms. Therapeutic tools include surgery, interventional radiology and medical treatments such as somatostatin analogues, interferon, chemotherapy, new targeted drugs and peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues [Modlin 2008]. Several clinical trials have indicated that PRRT with somatostatin analogues 90Y-DOTATOC, 177Lu-DOTATATE and 177Lu-DOTATOC, is an efficient tool in the management of NETs (30% objective responses with a great survival benefit) which compares favorably to classic chemotherapy results (up to 20% responses) [Kwekkeboom 2005].
Dosimetric studies demonstrated that these radiopeptides are able to deliver high radiation doses to somatostatin receptor sst2-expressing tumors and acceptable doses to normal organs [Cremonesi 2010]. Side effects, usually mild, may involve kidneys and bone marrow. Renal protection is used to minimize the risk of a late function decrease [Bodei 2003].
Pts are selected for PRRT based on molecular imaging with 111In-pentetreotide or, more recently, a 68Ga-SSA-PET, such as 68Ga-DOTATOC/DOTATATE/DOTANOC [Virgolini 2010], which have revolutionized the NET imaging, with an overall sensitivity of >90%, and specificity ranging from 92% to 98% [Ambrosini 2012].
PRRT is an innovative therapeutic approach for inoperable or metastasized, well/moderately differentiated GEP and bronchial NETs. PRRT in P-NETs has demonstrated efficacy in terms of objective response and impact on survival parameters. Since surgery is the only curative option for patients with GEP-NETs, it is proposed that neoadjuvant treatment will improve outcome by enabling disease regression that will enable surgical resection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients affected by unresectable or borderline resectable P-NETs and limited liver disease
- •Multidisciplinary evaluation in which a global therapy approach is proposed with PRRT in a neoadjuvant setting.
- •Histopathologic diagnosis of WHO G1/G2 P-NET
- •Conserved hematological, liver and renal parameters: hemoglobin >/= 10 g/dL, absolute neutrophil count (ANC) >/= 1.5 x 109 /L, platelets >/= 100 x 109 /L, bilirubin </= 1.5 X UNL (upper normal limit), ALT < 2.5 X UNL (< 5 X UNL in presence of liver metastases), creatinine < 2 mg/dL.
- •Age more than 18 years.
- •Patients with documented disease will be admitted to therapeutic phase only if the diagnostic receptor imaging (Ga-68-peptides PET/CT or OctreoScan) demonstrate a significant uptake in the tumor (grade 2 or 3, according to a preset scoring, where grade 1= equal to normal liver, grade2 = higher than normal liver, grade 3= higher than kidneys and spleen), that may allow delivering a low absorbed dose to normal organs and a high dose to the tumor [Cremonesi 1999, Cremonesi 2010].
- •Disease must be measurable by means of conventional imaging (CT or MRI)
- •Before treatment clinical history data will be collected, physical examination will be performed and diagnostic and laboratory data will be examined.
- •Patients must not receive other treatments (e.g. chemo- or radiotherapy) from one month before to two months after the completion of 90Y-DOTATOC cycles.
- •Patients must be naive from previous radionuclide treatments with radiopeptides (e.g. 111Inpentetreotide, Lu-177-petides) or other radiopharmaceuticals (e.s. 131I-MIBG, 131I).
排除标准
- •- Pregnancy/breastfeeding (a pregnancy test not older than 7 days is mandatory).
- •Assessed bone marrow invasion > 25%.
- •Other concomitant neoplasm (excluding in situ basaliomas and radically treated cervical cancers).
- •ECOG score higher than
- •Expectancy of life shorter than 6 months.
- •Patients with psycho-physical conditions that are not suitable for entering this clinical study and fulfilling its requirements.
- •No multidisciplinary indication to surgery after PRRT
研究组 & 干预措施
Y-90-DOTATOC
Patients will receive PRRT with Y-90-DOTATOC
干预措施: peptide receptor radionuclide therapy with Y-90-DOTATOC (Drug)
结局指标
主要结局
objective response evaluation
时间窗: 6 months after end of PRRT
objective responses (partial and complete responses, stable disease) will be evaluated according to modified RECIST criteria (mRECIST).
次要结局
- analysis of tumor specific circulating NET transcripts(before PRRT, and 3 and 6 months after therapy.)
- rate of operability(3 months after the end of PRRT.)